The broad, long-term objective of this laboratory is to improve fetal, neonatal and adult cardiac health by discovering the mechanisms regulating cardiac development. Epidemiological research links the adult development of coronary heart disease to events in the fetal period. The relationship between cardiomyocyte and coronary growth in the fetal period ultimately determines maximal coronary reserve, an important risk factor in the adult. Altered fetal myocardial oxygen demand is a common element in normal hearts as it is in conditions of placental insufficiency, fetal hypoxia, congenital malformations that increase cardiac work, and fetal anemia. The driving stimulus synchronizing coronary growth to cardiomyocyte growth in utero is likely to be oxygen, but the underlying mechanisms by which oxygen levels might provide a stimulus for coronary remodeling is not known. Solving this gap in our knowledge would enable us to develop strategies for diagnosing and correcting the cardiomyocyte-capillary mismatch that may underlie vulnerability for disease. We propose that brief periodic mismatches in oxygen demand vs. supply provide signals that link fetal coronary vascular growth to cardiomyocyte growth. We have developed a working model that links coronary to cardiomyocyte growth through specific chemical signals, from which we propose the following specific aims: 1) Determine the degree to which myocardial oxygen demand regulates fetal coronary vascular growth. 2) Determine the degree to which adenosine signaling regulates fetal coronary growth during increased myocardial oxygen demand. 3) Determine how chronically increased oxygen demand potentiates adenosine and VEGF signaling by regulation of pathway components. These aims will be tested in a chronically instrumented fetal sheep model in which cardiac oxygen demand is increased by the innovative application of a mitochondrial uncoupling agent. In order to determine the importance of adenosine signaling for the adaptive process of coronary growth, and adenosine receptor antagonist will also be employed in this model. Coronary reserve will be used to test for coronary growth in vivo, while morphometric techniques will be used to precisely quantify changes in specific vessel beds. Molecular and enzyme assays will be called upon to determine how critical pathways are regulating fetal coronary growth. Understanding the role of myocardial oxygen demand as a determinant of fetal coronary vascular growth will lead to recognition and treatment of fetal conditions that will impact coronary flow reserve and cardiovascular health for life. PUBLIC HEALTH RELEVANCE: The direct and indirect economic costs of cardiovascular disease in the U.S. are staggering, but despite this expenditure coronary heart disease remains the leading cause of death. Much adult disease has its origins in the fetal environment, and we suggest that fetal coronary development is a critical and overlooked risk factor for adult disease. This project probes a mechanism that may regulate coronary development in all pregnancies.